Patent GB-998552-A (GB)
Title: Substituted phenylalkanes and preparation thereof
IPC: A61K31/135
Filed: 1964-04-06
Abstract: The invention comprises compounds of the formula <FORM:0998552/C2/1> (wherein the tertiary alkyl group contains 4 to 6 carbon atoms, the benzene ring being optionally additionally mono- or di-substituted by methyl or ethyl groups; R1 is hydrogen or C1-4 alkyl; and R2 is hydrogen, C1-6 alkyl, C7-12 aralkyl which may be substituted in the aromatic ring by 1 to 3 hydroxy, methoxy or ethoxy groups or by a methylenedioxy group, a C2-3 hydroxyalkyl group or a C7-11 phenoxyalkyl group) and acid-addition salts thereof; and their preparation (1) by reducing a compound of the formula <FORM:0998552/C2/2> wherein the phenyl group is substituted as in compounds I, X is =O or H, OH and Y is -CHR1.NHR2 or a group convertible thereto by reduction and, if desired, radicals which can be eliminated by hydrogenolysis are present instead of hydrogen atoms, provided that X and Y only simultaneously denote H, OH and -CHR1.NHR2 when there is at least one radical present which can be eliminated by hydrogenolysis; or (2) by reacting a compound of the formula <FORM:0998552/C2/3> (wherein the phenyl group is substituted as in compounds (I), R3 is hydroxy and R4 is chlorine or bromine or R3 and R4 together are an oxygen atom) with the appropriate amine R2NH2 or a compound capable of yielding this amine; or (c) treating a compound of formula (I) which contains one or two functionally modified hydroxyl groups and/or in which the amino group is present in a functionally modified form or which has the group <FORM:0998552/C2/4> instead of the group -CHOH.CHNHR2 to liberate the free hydroxyl and/or amino groups by hydrolysis, alcoholysis or aminolysis; or (d) by alkylating the corresponding primary amines (i.e. compounds (I) wherein R2 is hydrogen). Groups convertible by reduction to the group -CHR1.NHR2 are -CR1NOH or esters thereof, -CHR1.N3, -CN, -CHR1.NO2, -CHR1NHNH2 or substituted derivatives thereof, -C(R1)=N.NH2 or substituted derivatives thereof, -CONH2, -C(R1)=NR2, -CHR1.N=R1, -CHR1.NH.R1.OH and -CHR1.NH.acyl wherein R1 is alkylidene, aralkylidene, hydroxyalkylidene or phenoxyalkylidene. Radicals which can be eliminated by hydrogenolysis are N-benzal groups, O- or N-benzyl groups which may be substituted, carbobenzoxy groups, nitroso groups, amino groups, arylsulphonyl groups and halogen atoms.  An extensive list of reducing agents is provided. Processes (a) and (b) may also be effected simultaneously.  In process (c), functionally modified hydroxyl groups include acyloxy or other ester groups and alkoxy groups and functionally modified amino groups include acylated amino groups (including arylsulphonylamino), or isocyanate or nitrosamino groups.  In process (d) direct or reductive alkylation may be used.  The products may be resolved into optically active forms and separated into erythro and threo forms. Examples are given and a list of salt-forming organic and inorganic acids is provided.  Compounds of the formula (II) are prepared from the corresponding a -bromo-ketones (prepared by reacting appropriately substituted phenols with alkyl halides to give, after hydrolysis of the phenol esters of the ketones first formed, substituted phenyl alkyl ketones, and then brominating these) and the appropriate amines or protected, e.g. benzylated, amines.  They may then be, for example, debenzylated. o  - Amino - 3 - t. - butyl - 4 - hydroxy - 5 - methyl - acetophenone hydrochloride is also formed when the corresponding azide is hydrogenated.  The aforementioned azide and other similar azides are prepared from the corresponding a -bromoketones and sodium azide. 3-Hydroxy-4-t.-butyl-acetophenone is prepared by nitrating p-t.-butyl-acetophenone to give 3-nitro-4-t.-butyl-acetophenone, reducing this to the 3-amino-compound and diazotizing and boiling this. 3-Benzyloxy-4-t.-butyl-acetophenone is prepared by benzylation. 3-Benzyloxy-4-t.-butyl-2,6-dimethyl-acetophenone is prepared by reacting the corresponding benzaldehyde with methyl magnesium iodide and then oxidizing the product a -isonitroso-3-t.-butyl-4-hydroxy-5-methyl-propiophenone is prepared from the a -unsubstituted ketone and hydrogen chloride and methyl nitrite. 2-Methyl-4-bromo-6-t.-amyl-phenol is prepared from 2-methyl-4-bromophenol and t.-amyl alcohol or amylene. 3-Benzyloxy-4 - t. - butyl - 2,6 - dimethyl-benzaldehyde is prepared by acetylation, saponification and benzylation of 3-hydroxy-4-t.-butyl-2,6-dimethylbenzyl chloride to give 3-benzyloxy-4 - t. - butyl - 2,6 - dimethyl - benzyl alcohol and then oxidation of this. 1-(31-t.-butyl-41-propionyloxy - 51 - methylphenyl) - 1 - hydroxy - 2 - methylamino-propane hydrochloride is prepared by reaction of a -bromo-3-t.-butyl-4-propionyloxy-5-methyl-propiophenone with N-benzyl- N - methylamine to give a  - (N - benzyl - N - methylamino) - 3 - t. - butyl - 4 - propionyloxy- 5 - methyl - propiophenone hydrochloride and then hydrogenation of this.  The substituted aminodiols of the invention, which are stated variously to have hypertensive, bronchospasmolytic, vascoconstricting, anorectic, analeptic and sympathicomimetic action, may be made up into pharmaceutical compositions with suitable carriers.  They may take the form of solutions, suspensions, emulsions, implants, tablets, dragees, ointments or creams and may contain preservatives, stabilizers, wetting agents, salts for controlling osmotic pressure or buffers.